Drugs in pharmaceutical compositions can be prepared in a variety of different forms. Such drugs can be prepared so as to have a variety of different chemical forms including chemical derivatives or salts. Such drugs can also be prepared to have different physical forms. For example, the drugs may be amorphous or may have different crystalline polymorphs, perhaps existing in different solvation or hydration states. By varying the form of a drug, it is possible to vary the physical properties thereof. For example, crystalline polymorphs typically have different solubilities from one another, such that a more thermodynamically stable polymorph is less soluble than a less thermodynamically stable polymorph. Pharmaceutical polymorphs can also differ in properties such as shelf-life, bioavailability, morphology, vapor pressure, density, color, and compressibility. Accordingly, variation of the solvation state of a drug is one of many ways in which to modulate the physical properties thereof.
A solvate may be defined as a compound formed by solvation, for example as a combination of solvent molecules with molecules or ions of a solute. Well known solvent molecules include water, alcohols and other polar organic solvents. Alcohols include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, and t-butanol. Alcohols also include polymerized alcohols such as polyalkylene glycols (e.g., polyethylene glycol, polypropylene glycol). The best-known and preferred solvent is typically water, and solvate compounds formed by solvation with water are termed hydrates.
Propylene glycol (1,2-propanediol) is a known substance which is a liquid at ambient temperature. As far as the applicants are aware, propylene glycol is not generally well-known for use in the formation of solvates. U.S. Pat. No. 3,970,651 does disclose the use of propylene glycol in the formation of a crystalline cephalosporin derivative. According to this disclosure a propylene glycolate derivative of a specific cephalosporin zwitterion may be formed in the presence of propylene glycol at acidic pH. This disclosure indicates that the propylene glycol derivative is more stable in solid form than the corresponding ethanolate, especially having excellent colour stability and thermal stability. No other solvates are disclosed in this US patent other than the specific solvate of cephalosporin.
In pharmaceutical formulations certain chemical classes of drugs pose particular problems in preparing pharmaceutical formulations for medical use. One such problem arises in the case of hygroscopic drugs, which tend to absorb water from the air. This is disadvantageous because it makes storage of the drug difficult and can cause degradation of the drug in some cases. Such compounds must be handled in controlled humidity environments during manufacture in order to prevent potency errors due to the changing weight of the drug. The final product must be packaged in individual moisture resistant blisters in order to prevent changes in or degradation of the product. Another problem arises from variable hydration states: molecules may change to a more or less stable form as water, a volatile liquid, is lost. Such changes have been known to cause some hydrates to become amorphous. Likewise, absorption of water by a hygroscopic molecule can plasticize the system and lead to recrystallization as a less stable polymorph.